- Synthesis, computational studies, tyrosinase inhibitory kinetics and antimelanogenic activity of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives
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The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives 3a–e and 5a–e as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives 3a–e and 5a–e was determined and it was found that derivative 5c possesses excellent activity with IC50 = 0.0089 μM compared to standard kojic acid (IC50 = 16.69 μM). The presence of hydroxyl groups at the ortho and the para position of cinnamic acid phenyl ring in compound 5c plays a vital role in tyrosinase inhibitory activity. The compound 5d also exhibited good activity (IC50 = 8.26 μM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound 5c is a competitive inhibitor while 5d is a mixed-type inhibitor. The mode of binding for compounds 5c and 5d with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative 5c formed stable complex with target protein. The cytotoxicity results showed that compound 5c is safe at a dose of 12 μg/mL against murine melanoma (B16F10) cells. The same dose of 5c was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound 5c may serve as a lead structure to design more potent antimelanogenic agents.
- Rafiq, Muhammad,Nazir, Yasir,Ashraf, Zaman,Rafique, Hummera,Afzal, Samina,Mumtaz, Amara,Hassan, Mubashir,Ali, Anser,Afzal, Khurram,Yousuf, Muhammad Rizwan,Saleem, Muhammad,Kotwica-Mojzych, Katarzyna,Mojzych, Mariusz
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- Phosphonate as a Stable Zinc-Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
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Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc-binding group (ZBG) variants of this thiol-derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development.
- Voos, Katrin,Sch?nauer, Esther,Alhayek, Alaa,Haupenthal, J?rg,Andreas, Anastasia,Müller, Rolf,Hartmann, Rolf W.,Brandstetter, Hans,Hirsch, Anna K. H.,Ducho, Christian
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p. 1257 - 1267
(2021/03/24)
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- Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors
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Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Thus, nineteen new quinazoline-4(3H)-one derivatives were designed and synthesized. Preliminary cytotoxicity studies of the synthesized compounds were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Five compounds were found to have promising cytotoxic activities against all cell lines. Compound 16f, containing a 2-chloro-5-nitrophenyl group, has emerged as the most active member. It was approximately 4.39-, 5.73- and 1.96-fold more active than doxorubicin and 3.88-, 5.59- and 1.84-fold more active than sorafenib against HepG2, HCT-116 and MCF-7 cells, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. The results of in vitro VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Molecular docking of these compounds into the kinase domain, moreover, supported the results.
- El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Ayyad, Rezk R.,Mahdy, Hazem A.,Khalifa, Mohamed M.,Elnagar, Hamdy A.,Mehany, Ahmed B.M.,Metwaly, Ahmed M.,Elhendawy, Mostafa A.,Radwan, Mohamed M.,ElSohly, Mahmoud A.,Eissa, Ibrahim H.
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- Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities
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Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
- Abdel Gawad, Nagwa M.,El Kerdawy, Ahmed M.,George, Riham F.,Georgey, Hanan H.,Mohamed, Abdalla R.
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- Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection
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Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
- Li, Qi,Chen, Ying,Xing, Shuaishuai,Liao, Qinghong,Xiong, Baichen,Wang, Yuanyuan,Lu, Weixuan,He, Siyu,Feng, Feng,Liu, Wenyuan,Chen, Yao,Sun, Haopeng
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p. 6856 - 6876
(2021/05/29)
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- New quinoxaline-2(1H)-ones as potential VEGFR-2 inhibitors: design, synthesis, molecular docking, ADMET profile and anti-proliferative evaluations
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Eleven new quinoxaline derivatives were designed and synthesized as modified VEGFR-2 inhibitors of our previous work. The synthesized compounds were tested against three human cancer cell lines (HepG-2, MCF-7 and HCT-116). Compounds11g,11eand11cwere the most potent members against the tested cells. Compound11g(IC50= 4.50, 2.40, and 5.90 μM) was the most potent member compared to doxorubicin (IC50= 8.29, 9.65, and 7.68 μM) and sorafenib (IC50= 7.33, 9.41, and 7.23 μM) against HepG-2 and HCT-116, and MCF-7 cell lines, respectively. Compound11eshowed better anti-proliferative activities than doxorubicin and sorafenib with IC50values of 5.34, 4.19, and 6.06 μM, against HepG-2 and HCT-116 and MCF-7 cell lines, respectively. In addition, the most active anti-proliferative derivatives11c,11e,11f, and11gwere selected to evaluate their inhibitory activities against VEGFR-2. The tested compounds displayed good inhibitory activity with IC50values ranging from 0.75 to 1.36 μM. Among them, compound11gwas the most active member with an IC50value of 0.75 μM, compared to the reference drug; sorafenib (IC50= 1.29 μM). Moreover, docking studies revealed that the synthesized compounds have good binding patterns against the prospective molecular target; VEGFR-2. In addition,in silico, ADMET and toxicity studies showed a high level of drug likeness for the synthesized compounds.
- Abulkhair, Hamada S.,Eissa, Ibrahim H.,El-Adl, Khaled,ElSohly, Mahmoud A.,Elhendawy, Mostafa A.,Mehany, Ahmed. B. M.,Metwaly, Ahmed M.,Radwan, Mohamed M.,Sakr, Helmy M.,Yousef, Reda G.
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p. 16949 - 16964
(2021/09/27)
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- Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
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Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26b, 29a, 29b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 μM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC50 value of 2.5 ± 0.04 μM, almost equal to that of sorafenib (IC50 = 2.4 ± 0.05 μM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities.
- Belal, Amany,Eissa, Ibrahim H.,El-Gamal, Kamal M. A.,El-Sharkawy, Abdou,Elhendawy, Mostafa A.,Elsohly, Mahmoud A.,Ibrahim, Mohammed K.,Mahdy, Hazem A.,Mehany, Ahmed B. M.,Metwaly, Ahmed M.,Radwan, Mohamed M.
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- Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors
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Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 μM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 μM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.
- Khalifa, mohamed m.,Radwan, mohamed m.,Rashed, mahmoud,Sakr, Helmy,ayyad, Rezk R.,belal, amany,eissa, Ibrahim H.,el-Helby, abdel-Ghany a.,el-Sharkawy, abdou,elSohly, mahmoud a.,elhendawy, mostafa a.,mahdy, Hazem a.,metwaly, ahmed m.
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- Discovery of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors: Design, synthesis, and anti-proliferative evaluation
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Sixteen novel quinazoline-based derivatives were designed and synthesized via modification of the VEGFR-2 reported inhibitor 7 in order to increase the binding affinity of the designed compounds to the receptor active site. The designed compounds were evaluated for their VEGFR-2 inhibitory effects. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. The bioactivity of the new compounds was performed against HepG-2, MCF-7 and HCT-116 cell lines. Doxorubicin and sorafenib were used as positive controls. Compound 18d was observed to have promising cytotoxic activity (IC50 = 3.74 ± 0.14, 5.00 ± 0.20 and 6.77 ± 0.27 μM) in comparison to the reference drug doxorubicin (IC50 = 8.28, 9.63 and 7.67 μM) and sorafenib (IC50 = 7.31, 9.40 and 7.21 μM). The most active compounds were tested for their in vitro VEGFR-2 inhibitory activities. Results of VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Thus, compound 18d showed VEGFR-2 inhibitory activity (IC50 = 0.340 ± 0.04 μM) superior to that of the reference drug, sorafenib (IC50 = 0.588 ± 0.06 μM). Furthermore, docking study was performed in order to understand the binding pattern of the new compounds into VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Glu883 and Asp1044, as well as their hydrophobic interaction with the receptor hydrophobic pocket. Results of cytotoxic activities, in vitro VEGFR-2 inhibition together with docking study argument the advantages of the synthesized analogues as promising anti-angiogenic agents.
- Eissa, Ibrahim H.,El-Helby, Abdel-Ghany A.,Mahdy, Hazem A.,Khalifa, Mohamed M.,Elnagar, Hamdy A.,Mehany, Ahmed B.M.,Metwaly, Ahmed M.,Elhendawy, Mostafa A.,Radwan, Mohamed M.,ElSohly, Mahmoud A.,El-Adl, Khaled
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- Selective cyclooxygenase inhibition and ulcerogenic liability of some newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine scaffold
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Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l)were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-[7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo[4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g)was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC50 = 0.87–3.78 μM), in particular, the derivatives 9e (IC50 = 0.92 μM), 9g (IC50 = 0.87 μM)and 9k (IC50 = 1.02 μM)recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC50 = 1.11 μM). The in vivo potent compounds (9e, 9g and 9k)caused variable ulceration effect (ulcer index = 5–12.25)in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k)to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme.
- Bakr, Rania B.,Ghoneim, Amira A.,Azouz, Amany A.
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- Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR-2 inhibitors
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Novel series of benzoxazoles 4a-f-16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5e was found to be the most potent against HepG2, HCT-116, and MCF-7 with IC50 = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 μM, respectively. Compounds 5c, 5f, 6b, 5d, and 6c showed the highest anticancer activities against HepG2 cells with IC50 of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 μM, respectively; HCT-116 cells with IC50 of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 μM, respectively; and MCF-7 cells with IC50 of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 μM, respectively, compared with sorafenib as a reference drug with IC50 of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 μM, respectively. The most active compounds 5c-f and 6b,c were further evaluated for their vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition. Compounds 5e and 5c potently inhibited VEGFR-2 at lower IC50 values of 0.07 ± 0.01 and 0.08 ± 0.01 μM, respectively, compared with sorafenib (IC50 = 0.1 ± 0.02 μM). Compound 5f potently inhibited VEGFR-2 at low IC50 value (0.10 ± 0.02 μM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR-2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
- El-Helby, Abdel-Ghany A.,Sakr, Helmy,Eissa, Ibrahim H.,Abulkhair, Hamada,Al-Karmalawy, Ahmed A.,El-Adl, Khaled
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- Pharmacological and physicochemical profile of arylacetamides as tools against human cancers
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Arylacetamides are widely used as synthetic intermediates to obtain medicinal substances. This work evaluated in vitro antiproliferative activity of ten 2-Chloro-N-arylacetamides on human normal and cancer cells and detailed in vivo toxicological and anticancer investigations. Initially, cytotoxic colorimetric assays were performed using tumor lines, peripheral blood mononuclear cells (PBMC) and erythrocytes. Compounds 2, 3 and 4 were tested for acute toxicity (50, 150 and 300 mg/kg) and for subacute antitumoral capacity in HCT-116 colon carcinoma-bearing xenograft mice for 15 days at 25 mg/kg/day. Most compounds revealed cytotoxic action on tumor lines and PBMC, but activity on human erythrocytes were not detected. Molecular dipole moment, lipophilicity and electronic constant of aryl substituents had effects upon in vitro antiproliferative capacity. More common in vivo acute behavioral signals with compounds 2, 3 and 4 were muscle relaxation, reduction of spontaneous locomotor activity and number of entries in closed arms and increased number of falls andtime spent in open arms, suggesting diazepam-like anxiolytic properties. Decrease of grabbing strength and overall activity were common, but palpebral ptosis and deaths occurred at 300 mg/kg only. Compounds 2 and 3 reduced colon carcinoma growth (21.2 and 27.5%, respectively, p 0.05) without causing apparent signals of organ-specific toxicity after subacute exposure. The structural chemical simplicity of arylacetamides make them cost-effective alternatives and justifies further improvements to enhance activity, selectivity and the development of pharmaceutical formulations.
- Ferreira, Paulo Michel Pinheiro,Machado, Kátia da Concei??o,Lavorato, Stefania Neiva,de Oliveira, Fátima de Cássia Evangelista,Silva, Jurandy do Nascimento,de Almeida, Antonia Amanda Cardoso,Santos, Luciano de Souza,Silva, Valdenizia Rodrigues,Bezerra, Daniel Pereira,Soares, Milena Botelho Pereira,Pessoa, Cláudia,de Moraes Filho, Manoel Odorico,Ferreira, José Roberto de Oliveira,Sousa, Jo?o Marcelo de Castro e,Maltarollo, Vinícius Gon?alves,Alves, Ricardo José
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- Discovery of novel AHLs as potent antiproliferative agents
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Three series of novel AHL analogs were synthesized and evaluated for their in vitro cytotoxic activity against four human cancer cell lines. The SARs investigation indicated that AHLs with a terminal phenyl group, especially those with the chalcone scaffold had remarkably enhanced cytotoxicity than those with the hydrophobic side chains. Besides, some of these compounds were much more potent than 5-Fu and natural OdDHL. Through the detailed SARs discussions, we found that compounds 10a-k and 14 with the 4-amino chalcone scaffold showed excellent inhibition against all the tested cancer cell lines and were much more potent than 5-Fu and AHLs. Such scaffold may act as a template for further lead optimization. Compound 10i with a 3, 4, 5-trimethoxy group was the most potent one against all the tested cancer cell lines. Flow cytometry analysis indicated that analog 11e induced the cellular apoptosis and cell cycle arrest of MCF-7 cells at G2/M phase in a concentration-and time-dependent manner.
- Ren, Jing-Li,Zhang, Xu-Yao,Yu, Bin,Wang, Xi-Xin,Shao, Kun-Peng,Zhu, Xiao-Ge,Liu, Hong-Min
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p. 321 - 329
(2015/03/04)
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- Synthesis and in vitro kinetic study of novel mono-pyridinium oximes as reactivators of organophosphorus (OP) inhibited human acetylcholinesterase (hAChE)
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A series of mono pyridinium oximes linked with arenylacetamides as side chains were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by organophosphorus inhibitors (OP) such as sarin, VX and tabun. The reactivation data of the synthesized compounds were compared with those obtained with standard reactivators such as 2-PAM and obidoxime. The dissociation constant (KD) and specific reactivity (kr) of the oximes were also determined by performing reactivation kinetics against OP inhibited hAChE. Among the synthesized compounds, oximes 1-(2-(4-cyanophenylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (12a) and 4-((hydroxyimino)methyl)-1-(2-(4-methoxyphenylamino)-2-oxoethyl)pyridinium chloride (2a) were found most potent reactivators for hAChE inhibited by sarin. In case of VX inhibited hAChE majority of the oximes have shown good reactivation efficacies. Among these oximes 1-(2-(benzylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (18a), 4-((hydroxyimino)methyl)-1-(2-(4-(methoxycarbonyl)phenylamino)-2-oxoethyl)pyridinium-chloride (14a) and 12a were found to surpass the reactivation potential of 2-PAM and obidoxime. However, the synthesized oximes showed marginal reactivation efficacies in case of tabun inhibited hAChE. The pKa value of the oximes were determined and correlated with their observed reactivation potential.
- Valiveti, Aditya Kapil,Bhalerao, Uma M.,Acharya, Jyotiranjan,Karade, Hitendra N.,Gundapu, Raviraju,Halve, Anand K.,Kaushik, Mahabir Parshad
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p. 125 - 132
(2015/06/25)
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- Chloroquinoline-acetamide hybrids: A promising series of potential antiprotozoal agents
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In an endeavour to develop efficacious antiprotozoal agents 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]acetamide derivatives were synthesized and screened in vitro against the HM1:IMSS strain of E. histolytica and 3D7 strain of P. falciparum. Among the twenty-seven synthesized compounds, eleven evinced propitious anti-amoebic activity with IC50 values ranging from 0.41 to 1.80 μM) lower than the standard drug metronidazole (IC50 1.80 μM). All the compounds inhibited the in vitro growth of P. falciparum (IC50 range: 0.30-33.52 μM). Compounds A22 and A25 were found to be the most active antimalarial derivatives, and compound A16 the most active in inhibiting β-haematin formation; however compound A25 displayed the more favourable safety profile. The crystal structure for the compounds A7, A8, A12 and A21 was also determined. The molecular docking of crystal resolved inhibitors with PfDHFR allowed identification of stabilizing interactions within enzyme active sites. These compounds affirm the potential for further derivatives to enhance antiprotozoal activity whilst retaining their safety profile.
- Inam, Afreen,Van Zyl, Robyn L.,Van Vuuren, Natasha J.,Chen, Chien-Teng,Avecilla, Fernando,Agarwal, Subhash M.,Azam, Amir
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p. 48368 - 48381
(2015/06/16)
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- Synthesis and antimicrobial evaluation of 1,3,4-oxadiazole-based chalcone derivatives
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A series of chalcones-bearing 1,3,4-oxadiazole derivatives was synthesized as novel bio-active antimicrobial agents against multidrug-resistant bacteria and fungi. The lead compounds (Z)-2-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-ylthio) -N-(4-(3-(aryl)acryloyl)phenyl)acetamides 5a-n were synthesized via acid-catalyzed aldol condensation (SOCl2) by reacting N-(4-acetylphenyl)-2-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-ylthio)acetamide (4) with differently substituted aldehydes. Compound (4) was obtained by reacting 5-(3-nitrophenyl)-1,3,4-oxadiazole-2-thiol (2) with N-(4-acetylphenyl)-2- chloroacetamide (3) in the presence of K2CO3. The intermediates (2) and (3) were synthesized simultaneously from 3-nitrobenzohydrazide (1) and 4-aminoacetophenone, respectively. The formation of intermediates and targeted compounds were confirmed for their structure by means of various spectral-analytical techniques like IR, 1H NMR, 13C NMR, elemental analysis, and mass spectra. Antimicrobial properties of all the synthesized compounds have been evaluated against broad panel of bacteria and fungi. Springer Science+Business Media 2013.
- Joshi, Deepkumar,Parikh, Kalpesh Suryakant
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p. 1855 - 1864
(2014/05/06)
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- Narrow SAR in odorant sensing Orco receptor agonists
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The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification.
- Romaine, Ian M.,Taylor, Robert W.,Saidu, Samsudeen P.,Kim, Kwangho,Sulikowski, Gary A.,Zwiebel, Laurence J.,Waterson, Alex G.
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p. 2613 - 2616
(2014/06/09)
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- Narrow SAR in odorant sensing Orco receptor agonists
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The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification.
- Romaine, Ian M.,Taylor, Robert W.,Saidu, Samsudeen P.,Kim, Kwangho,Sulikowski, Gary A.,Zwiebel, Laurence J.,Waterson, Alex G.
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p. 2613 - 2616
(2015/02/19)
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- Synthesis, characterization and antimicrobial activity of 2-(11-oxodibenzo [b,f][1,4]thiazepin-10(11H)-yl)-N (substituted phenyl) acetamide derivatives
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Substituted dibenzo [b,f][1,4]thiazepines analogues carrying 2-chloro N-phenylacetamide moiety attached to 11-C position have been synthesized and evaluated using IR, 1H NMR and mass spectra. Antibacterial properties have been examined for the synthesized derivatives against gram positive and gram negative bacteria. 2-(11-Oxodibenzo [b,f][1,4]thiazepin-10(11H)-yl)-N phenylacetamide derivatives show good significant antimicrobial activity.
- Tailor, Jitesh H.,Patel, Priti C.,Malik
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p. 1263 - 1268
(2014/12/10)
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- Antibacterial and antifungal screening of newly synthesized benzimidazole-clubbed chalcone derivatives
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Different derivatives of chalcone-possessing benzimidazole as a prime motif were synthesized by the authors by acid catalyzed aldol condensation reaction. The synthesis of the desired compounds was initiated by undertaking two parallel reactions: (i) synthesis of 2-mercaptobenzimidazole and (ii) synthesis of N-(4-acetylphenyl)-2-chloroacetamide from 4-aminoacetophenone. The two intermediates so prepared were condensed to yield 2-(1H-benzo[d]imidazol-2- ylthio)-N-(4-acetylphenyl)acetamide (II) using acetone as solvent and K 2CO3 as a scavenger. The resultant product was further reacted with differently substituted aldehydes to produce the titled compounds using thionyl chloride (SOCl2) in catalytic amount. The synthesized compounds were confirmed for their structure by means of various spectrometric techniques like IR, 1H NMR, 13C NMR, Mass spectra, and Elemental analysis. Thus-obtained chalcone derivatives were tested for their antibacterial and antifungal activities and were reported in form of minimum inhibitory concentration values.
- Parikh, Kalpesh,Joshi, Deepkumar
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p. 3688 - 3697
(2013/07/26)
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- 4-Thiazolidinones in heterocyclic synthesis: Synthesis of novel enaminones, azolopyrimidines and 2-arylimino-5-arylidene-4-thiazolidinones
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The 4-thiazolidinones 3a-d were used as a key intermediates for the synthesis of 2-arylimino-5-arylidene-4-thiazolidinones derivatives 7a-p via nucleophilic addition reactions with the arylidene malononitrile. Moreover the 4-thiazolidinones 3a and 3c condensed with the DMF-DMA to form the corresponding enamines 8 and 9 depending on the reaction conditions. Otherwise the 4-thiazolidinone 3b reacts regioselectively with DMF-DMA to afford the enaminones 10 and 11, respectively. The latter reacts with many heterocyclic amines affording polyfunctionally substituted fused pyrimidine derivatives 13-18. The enamine 8b was also reacted with the 3-amino-1,2,4-triazole to afford the acyclic product 19, which could not be further cyclized to the corresponding tricyclic system 20. Moreover the 4-thiazolidinone 3c reacted with the benzenediazonium chloride to afford the arylhydrazones 12. The X-ray single crystal technique was employed in this study for structure elucidation and Z/E potential isomerism configuration determination. The X-ray crystallographic analyses of eight products could be obtained, thus establishing with certainty the structures proposed in this work.
- Behbehani, Haider,Ibrahim, Hamada Mohamed
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experimental part
p. 6362 - 6385
(2012/08/28)
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- Synthesis and biological evaluation of novel 5-benzylidenethiazolidine-2,4- dione derivatives for the treatment of inflammatory diseases
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Twenty-two compounds based on thiazolidine-2,4-dione moiety were synthesized and evaluated for the inhibitory potency on the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS) activity, and the generation of prostaglandin E2 (PEG2). (Z)-N-(3-Chlorophenyl)-2-(4- ((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acetamide (3I), superior to the commercial anti-inflammatory drug indomethacin, significantly inhibited iNOS activity (IC50 = 8.66 μM), iNOS-mediated NO, and cyclooxygenase (COX)-2-derived PGE2 production (IC50 = 4.16 and 23.55 μM, respectively) on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Docking study revealed that 3I was perfectly docking into the active site of murine iNOS and suppressed the expression of iNOS protein as evidenced by Western blot analysis. At the dose of 50 mg/kg, oral administration of 3I possessed protective properties in both carrageenan-induced paw edema and adjuvant-induced arthritis rat models.
- Ma, Liang,Xie, Caifeng,Ma, Yinghua,Liu, Juan,Xiang, Mingli,Ye, Xia,Zheng, Hao,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Chen, Jinying,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Liang, Xiaolin,Peng, Aihua,Yang, Shengyong,Wei, Yuquan,Chen, Lijuan
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supporting information; experimental part
p. 2060 - 2068
(2011/06/17)
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- Synthesis and biological activity of novel barbituric and thiobarbituric acid derivatives against non-alcoholic fatty liver disease
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Forty-four barbituric acid or thiobarbituric acid derivatives were synthesized and evaluated for their effects on adipogenesis of 3T3-L1 adipocytes by measuring the expression of adiponectin in vitro. Four compounds (3a, 3o, 3s, 4t) were found to increase the expression of adiponectin and lower the leptin level in 3T3-L1 adipocytes at respective concentration of 10 μM. Among them, 3s showed the most efficacious. Oral administration of 3s effectively reduced body weight, liver weight, and visceral fat and regulated serum levels of biochemical markers in the high-fat/diet-induced Wistar rats. Histopathological evaluation of liver sections by Oil Red O and H&E staining confirmed 3s as a potent, orally active molecule for reducing fat deposition against non-alcoholic fatty liver disease.
- Ma, Liang,Li, Shilin,Zheng, Hao,Chen, Jinying,Lin, Lin,Ye, Xia,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Peng, Aihua,Ding, Yi,Wei, Yuquan,Chen, Lijuan
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experimental part
p. 2003 - 2010
(2011/06/25)
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- SMALL MOLECULE CHOLINE KINASE INHIBITORS, SCREENING ASSAYS, AND METHODS FOR SAFE AND EFFECTIVE TREATMENT OF NEOPLASTIC DISORDERS
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Small molecule choline kinase inhibitors, pharmaceutical compositions thereof, and screening methods for identifying and evaluating choline kinase inhibitors are provided. Safe and effective methods for treating subjects suffering from a disorder or disease characterized by neoplastic cell proliferation employing the choline kinase inhibitors are also provided
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Page/Page column 18; 19
(2011/09/20)
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- Synthesis of α-chloroamides in water
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The reaction between chloroacetyl chloride and mono- or bis-aliphatic or aromatic amines in water under basic or neutral conditions gives rise to the formation of a variety of functionalized α-chloroamides. The resulting products were obtained as solids in moderate to good yields, upon precipitation and isolation by filtration.
- Harte, Andrew J.,Gunnlaugsson, Thorfinnur
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p. 6321 - 6324
(2007/10/03)
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- Synthesis of Some New &β-Lactams, 4-Thiazolidinones and Pyrazolines
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N-Arylidene-p-aminoacetophenone (I) and N-arylidene-4'-aminochalcones (V) have been converted into a series of substituted β-lactams (III) and 4-thiazolidinones (IV), and pyrazolines (VI, VII) respectively. p-Chloroacetamidoacetophenone (II) has also been converted into series of substituted 4'-piperidino/morpholinoacetoamidochalcones (X) which undergo cyclization on treatment with hydrazine, phenylhydrazine or thiourea to pyrazolines (XI, XII) and pyrimidine-2-thiones (XIII) respectively.The antibacterial and antifungal activities of the compounds have been determined.
- Fahmy, A. M.,Hassan, Kh. M.,Khalaf, A. A.,Ahmed, R. A.
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p. 884 - 887
(2007/10/02)
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